The alterations in the metabolism of drugs with aging not only pose a pharmaceutical problem but have far-reaching implications for immune response and carcinogenesis. Glutathione (GSH) and glutathione-S-transferase activity reflect a major pathway of drug metabolism that may be age related. Recent studies in this laboratory of CBF1 mice, long-lived models for the aging process, show that kidney and blood GSH peak at 12 to 18 months and then decline. We propose to study in mice 3-20 months old the effect of age on blood and tissue GSH, hepatic GSH perioxidase and S-transferase and glutathione turnover. The age-related changes in GSH metabolism are to be correlated with the rate at which acetaminophen depletes hepatic GSH, the induction of the mixed function oxidase appears sensitive to metal ions and thus, to glutathione depletion, the effect of penicillamine on GSH levels, GSH enzymes, and drug metabolism is to be investigated. A direct correlation of blood tissue GSH with altered drug metabolism has the potential of utilizing blood GSH as a clinical index of metabolic aging.